The objectives of the proposed research are to describe the properties of physiological pain modulating systems, and to apply recent advances in our understanding of these systems to the development of rational approaches to the management of pain. In the course of the research supported in previous years by this grant, we have studied over 1200 dental pain patients. In these studies we have demonstrated that even the most subtle cues can elicit a placebo response. Eliminating these cues by the use of preprogrammed machine infusion to blind the time of drug injection has allowed us to more accurately describe the time course of untreated postoperative pain (i.e., to develop a definitive natural history control). We have also provided evidence that the intensity of clinical pain is modulated by endogenous opioids (endorphins); that endogenous opioids can mediate placebo-induced analgesia; that opiate-induced analgesia exhibits properties similar to placebo analgesia, such as activation only after attainment of a threshold pain intensity; and that low doses of drugs acting at different sites in endogenous pain control systems can produce analgesia greater than the sum of the individual drug effects. We here propose to use knowledge of the mechanisms of action of various analgesic agents that act at mu and kappa opioid and non-opioid (serotonergic and noradrenergic) receptors in endorphinergic analgesia systems to design additional synergistic combinations of analgesics. In addition, the role of endorphinergic analgesia systems in determining the time course of narcotic induced analgesia will be studied by comparing the time course of the analgesia following drug administration to the time course of drug levels in the blood when the placebo component of the administration of the drug has been eliminated. Finally, we will use knowledge of the physiology of endorphinergic analgesia systems to determine the efficacy of patient-controlled analgesia-a popular new, and as yet poorly studied, treatment method in which the patient decides (within limits) the timing of narcotic administration. Taken together, these studies should lead to more rational approaches to the management of dental postoperative and other forms of pain.